The goal of this program project is to understand the nature of the pathways and processes that pattern the kidney epithelium into its terminally differentiated phenotype. Project 1 attempts to identify modifier loci in mice with targeted mutations in polycystin 1. Project 2 proposes to elucidate the molecular pathways that underlie the role of polycystin 1 in epithelial differentiation. Project 3 plans to characterize novel transcription factors thought to regulate renal tubulogenesis in vitro. Project 4 seeks to understand the genetic and physiologic factors influencing the course of cyst formation in Zebrafish. Project 5 seeks to understand the genetic and physiologic factors influencing the course of cyst formation in zebrafish. Project 5 intends to derive the three-dimensional structures of key domains in polycystin 1 and 2. Each of the projects is likely to yield fundamental insight into the biology of cyst formation, and provide new targets for therapeutic intervention. The objectives of this proposal and their common emphasis on molecular mechanisms invite a high degree of collaborative interactions and conceptual synergy best served by the program project format.